Abstract Delirium following cardiac surgery affects approximately 30-50% of patients, totaling 200,000 patients per year in this country alone, with patients over 70 years of age representing roughly 50% of those undergoing cardiac surgery. Perioperative delirium in the elderly cardiac surgical patient confers a significant morbid burden of poor functional and cognitive outcome, increased hospital length of stay and increased mortality. The public health impact of delirium in this population will likely only increase over time, making the development of effective approaches to prevention and treatment even more imperative. Further, there are accumulating data that oxidative damage and inflammatory response during cardiopulmonary bypass (CPB) contributes to postoperative organ dysfunction. Additionally, end organ dysfunction, morbidity and mortality have been linked to the deleterious effects of hyperoxia following ischemia-reperfusion injuries in several other disease states. In the current proposal we aim to leverage stored plasma samples collected as part of a prospective randomized controlled trial of patients randomized to one of two intraoperative ventilator management strategies in which the fraction of inspired oxygen is titrated to hyperoxia (100%) or normoxia (35%) conditions with corresponding blood oxygen levels, in order to undertake a nested, case control study. In this factorial design we will establish four matched cohorts of delirium positive, delirium negative, hyperoxia exposed and normoxia exposed patient samples and will apply state-of-the-art approaches, including advanced proteomics, to assess circulating proteins with a view towards biomarker discovery. Specifically, we aim to quantitatively assess the relationship between plasma inflammatory biomarker load with delirium and intraoperative hyperoxia, using advanced proteomic analysis, sampled at two intraoperative time points before and after CPB among patients 65 years old and over undergoing CABG surgery. Using this model we will seek to further elucidate the pathophysiological model related to delirium and hyperoxia, with the hope of identifying novel serum biomarkers that may be predictive of, interact with, or define delirium signatures. Results of the proposed analyses will provide the basis for further mechanistic studies to inform the development of prevention and treatment strategies for postoperative delirium in cardiac surgery and used to lessen the harmful impact of delirium in aging adults.